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源自胰腺癌细胞的外泌体通过miR125a - 5p/TNFRSF1B途径诱导破骨细胞分化。

Exosomes Derived from Pancreatic Cancer Cells Induce Osteoclast Differentiation Through the miR125a-5p/TNFRSF1B Pathway.

作者信息

Zhou Yizhao, Zhu Yi, Dong Xin, Cao Guodong, Li Yongzhou, Fan Yiqun, Chen Qing, Cai Haolei, Wu Yulian

机构信息

Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.

出版信息

Onco Targets Ther. 2021 Apr 19;14:2727-2739. doi: 10.2147/OTT.S282319. eCollection 2021.

DOI:10.2147/OTT.S282319
PMID:33907416
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8064725/
Abstract

BACKGROUND

Pancreatic cancer (PC) was regarded as the 4th principal cause of cancer-related fatalities in the United States and patients usually suffered from severe nutrition deficiency, muscle wasting, as well as bone loss. In our previous research, we have found that PC-derived exosomes potentially initiate insulin resistance in skeletal muscle cells. However, the role of exosomes in the PC-related bone loss remains unknown.

METHODS

The effect of PC-derived exosomes on the osteoclast differentiation and femoral bone structure in the orthotopic xenograft mouse model were investigated. MiRNA expression profiles were detected and a dual luciferase experiment was conducted to identify the direct target of miRNA.

RESULTS

Our data showed that PC-derived exosomes significantly induced osteoclast differentiation and increased expression of NFAT2, TRAP, CTSK and MMP-9. The bone volume fraction and trabecular thickness of femur significantly reduced in osteoporotic model. Microarray analyses and luciferase reporter assay showed that the process was, at least partially, mediated by the miR-125a-5p/TNFRSF1B signaling pathways.

CONCLUSION

According to the results, novel insights have been claimed the effect of exosomes derived from PC on bone deterioration and explained correlation between PC and cancer-related bone loss.

摘要

背景

胰腺癌（PC）被视为美国癌症相关死亡的第四大主要原因，患者通常患有严重的营养缺乏、肌肉萎缩以及骨质流失。在我们之前的研究中，我们发现源自胰腺癌的外泌体可能引发骨骼肌细胞中的胰岛素抵抗。然而，外泌体在胰腺癌相关骨质流失中的作用仍然未知。

方法

研究了源自胰腺癌的外泌体对原位异种移植小鼠模型中破骨细胞分化和股骨骨结构的影响。检测了miRNA表达谱，并进行了双荧光素酶实验以鉴定miRNA的直接靶标。

结果

我们的数据表明，源自胰腺癌的外泌体显著诱导破骨细胞分化，并增加了NFAT2、TRAP、CTSK和MMP-9的表达。骨质疏松模型中股骨的骨体积分数和小梁厚度显著降低。微阵列分析和荧光素酶报告基因检测表明，该过程至少部分由miR-125a-5p/TNFRSF1B信号通路介导。

结论

根据这些结果，人们对源自胰腺癌的外泌体对骨质恶化的影响有了新的认识，并解释了胰腺癌与癌症相关骨质流失之间的关联。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/515da16fa77a/OTT-14-2727-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/aaa18fc20349/OTT-14-2727-g0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/e94c7114baa8/OTT-14-2727-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/3b5ec36ef1ef/OTT-14-2727-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/14212718a5aa/OTT-14-2727-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/5ab1d2e8f0b8/OTT-14-2727-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/515da16fa77a/OTT-14-2727-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/aaa18fc20349/OTT-14-2727-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/653b3a0f5263/OTT-14-2727-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/685c42372c00/OTT-14-2727-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/6e548436727f/OTT-14-2727-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/e94c7114baa8/OTT-14-2727-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/3b5ec36ef1ef/OTT-14-2727-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/14212718a5aa/OTT-14-2727-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/5ab1d2e8f0b8/OTT-14-2727-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9f6/8064725/515da16fa77a/OTT-14-2727-g0009.jpg

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